Our research program addresses basic molecular and physiological processes of nociceptive transmission in the central nervous system. The molecular research is performed in animal and in vitro cell-based models. We concentrate on the primary afferent pain sensing neurons and their connections in the dorsal spinal cord. The dorsal spinal cord is the first site of synaptic connections for nociceptive information processing and our research has identified it as a locus of neuronal plasticity and altered gene expression in persistent pain states. Our aim is to understand the molecular and cell biological mechanisms of acute and chronic pain at the "entry level" in the nervous system. The regulation of transduction of physical pain stimuli is also under investigation using cloned thermal and chemo-responsive ion channels ectopically expressed in heterologous cell systems and naturally expressed in primary cultures of dorsal root ganglion. Novel methods for controlling nociceptive transmission that emerge from this basic research are addressed in a translational research program. Two main basic science issues are being investigated. The first centers on the molecular mechanisms of pain transduction through the vanilloid receptor 1 (TRPV1). This molecule is a heat-sensitive calcium/sodium ion channel and converts painful heat into nerve action potentials by depolarizing the pain sensing nerve terminals in the skin. Ion conductance is also stimulated by binding of capsaicin, a vanilloid compound and the active ingredient in hot pepper. This program has directly led to a bench to bedside application in which vanilloid agonists are used to kill pain-sensing neurons via ligand-induced calcium cytotoxicity and thereby provide pain control. The second program is centered on gene discovery in spinal cord. Subtraction cloning and differential hybridization has revealed new genes enriched in spinal cord and induced by pain stimuli. We are in the process of characterizing the known and novel genes. One gene has already been assessed due to its secretion into cerebrospinal fluid, in a human clinical protocol as a bio-marker for pain. Another is the receptor for neuropeptide FF which is known to be involved in opioid modulation of pain. This project is a long term, high-risk endeavor, which is setting new directions for molecular and clinical pain research. In addition to pain these studies fundamentally explore the molecular basis of synaptic plasticity in general, as we hypothesize a modularity in the neuronal response to a new level of synaptic or pharmacological input (e.g. learning, neurological disorders, drug abuse,). the translational studies are examining an ultrapotent vanilloid agonist, resiniferatoxin(RTX), as a pain control agent through removal of primary afferent pain sensing neurons. We developed an intraganglionic and intrathecal injection methods. The results demonstrate that RTX-induced pain cell deletion is a very effective approach to control of certain types of chronic pain especially those associated with cancer and arthritis.